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DOI 10.1007/s00417-012-2001-0
INFLAMMATORY DISORDERS
(Posiformin 2 %)
Pavel A. Bezdetko & Nikolai Sergienko & Yuriy Dyomin
Andrei Korol & Nik Nikitin & Matthias Merzbacher &
Dorothea Gro & Ralf Kohnen
&
Received: 17 October 2011 / Revised: 9 March 2012 / Accepted: 9 March 2012 / Published online: 25 April 2012
# The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract
Background Bibrocathol is a well-established antiseptic
drug for the treatment of acute eyelid diseases like blepharitis. Despite its frequent use in clinical practice, no controlled clinical trial on the efficacy of bibrocathol 2% eye
ointment has been performed until now. The aim of the
study was to investigate efficacy, safety and tolerability of
bibrocathol (Posiformin 2 %) eye ointment in patients
diagnosed with blepharitis.
Methods In this multi-center, randomized, doublemasked,
placebo-controlled parallel-group comparison, the change
of signs and symptoms (sum score) of blepharitis in 197
patients (ITT (intention-to-treat-group); mean age 56 18
years, 56 % female, active drug:vehicle 0 97:100) over 2
weeks treatment with bibrocathol 2 % eye ointment was
evaluated.
Results Patients receiving bibrocathol 2 % showed greater
improvement in the sum score than the placebo patients (p
<
Clinicaltrials.gov identifier: NCT01357538
P. A. Bezdetko
Department of Ophthalmology,
Kharkov District Clinical Hospital,
Kharkov, Ukraine
N. Sergienko
Department of Ophthalmology,
National Medical Academy
of postgraduate Education,
Kiev, Ukraine
Y. Dyomin
Post Diploma Education Academy,
Kharkov, Ukraine
A. Korol
The Filatov Institute of Eye Diseases and Tissue
1870
N. Nikitin
RUSSLAN
Clinical
Research
Ltd., North
Humberside,
UK
M. Merzbacher : R. Kohnen
RPS
Research
Germany
GmbH,
Nurember
g,
Germany
D. Gro (*)
URSAPHAR
M
Arzneimittel
GmbH,
Industriestrae
35,
66129
Saarbrc
ken,
German
y e-mail:
d.gross
@ursaph
arm.de
R. Kohnen
ReSearch
Pharmaceutical
Services Inc,
Fort Washington,
PA, USA
R. Kohnen
Psychology Department,
University of
ErlangenNuremberg,
Nuremberg,
Germany
79
80
maximum
discomfort. The four grading stages mentioned
above were clearly defined for each item and could
easily be assessed by the participating physicians; they
had been developed in a previous study [6]. Bacterial
growth was assessed in local site laboratories by analysis of palpebral smear, taken from the study eye lid,
with the following categories and scores: 0 0 no
growth of bacteria; 1 0 scattered growth of bacteria (< 7
germs);
2 0 moderate growth (750 germs) and 3 0
widespread growth (> 50 germs).
Safety parameters consisted of a visual acuity test (performed on V3 and V4), intra-ocular pressure (IOP) measu re me nt (V2 , V4) , ch an ge in co nc om ita nt oc
ul ar medication (V2, V3, V4), global tolerability
assessed by the patient and the investigator on a 4-point
scale with the highest figure indicating best tolerability
(V4), adverse events (V3, V4), and vital signs
examination (V3, V4).
Treatments were compared with respect to the efficacy
variables in an analysis of covariance (ANCOVA) model
with the factors of treatment and center. As baseline values
were additionally considered to have an influence on
changes from baseline, they were each included as covariates in the ANCOVA model. The treatment contrast was
presented by a least squares (LS) mean for the group
differ- ence together with its 95 % confidence interval (CI)
and the p value for the presumption that the contrast is 0.
Effect sizes (Cohens d) were presented for group
comparisons.
The absolute and relative frequencies as well as group
differences by Chi-squared tests were calculated for categorical variables. The last observation carried forward
meth- od (LOCF) for substitution of missing data was used
for an endpoint analysis in the primary and all secondary
outcome measures. In the modified intent-to-treat (ITT)
population, patients without post-baseline values for the
primary effica- cy variable were excluded from the
analysis. For all other patients, missing values of
signs/symptoms were replaced by the LOCF method (last
observation carried forward). Other missing values were
not replaced. Baseline character- istics were summarized
descriptively for the ITT sample. Safety and tolerability
variables were summarized descrip- tively for the safety
sample.
The sample size estimation was based on a similar
study with bibrocathol reporting an effect size of
Cohens d 0 0.43 for the difference to placebo with
a slightly different primary efficacy variable [8].
Assum- ing that the primary efficacy measure was as
sensitive as the outcome measure of the referenced trial,
86 patients per group were required to detect such an
effect size with a power of 90 % at the two-sided
significance level of 5 %. To account for non-evaluable
data due to drop-outs, 2 100 0 200 patients were to be
recruited for participation in this trial.
Results
A total number of two hundred patients was enrolled in
the trial, randomized, received bibrocathol 2 % (n 0 100)
or pla- cebo (n 0 100), and were available for safety and
tolerability analysis. Three patients were excluded from the
efficacy anal- ysis as they discontinued the study
prematurely without valid post-baseline data. Therefore, the
ITT population (for demo- graphic data see Table 1)
consisted of 197 patients.
Efficacy
Baseline mean values of the sum score were very similar in
both groups (bibrocathol: 10.4 points, placebo: 10.6
points). At V4 (LOCF) in both groups, the score was
reduced (raw values are given in Fig. 1); however, mean (
SD) reduction from baseline was larger in the group treated
with bibroca- thol (6.8 2.45 points) as compared to the
placebo group (4.6 3.33 points). Difference between
the treatment groups (LS mean) was 2.32 (95 % CI:
2.84; 1.80) favor- ing treatment with bibrocathol (p <
0.0001 from ANCOVA; Cohens d 0 0.73).
Baseline means in the four sub-scores were almost
equal between the two groups. Until V4 all
signs/symptoms im- proved to a larger extent under
bibrocathol than under placebo (for raw values see Fig. 2;
differences are given in Table 2).
Almost all patients had at least one severe or very
severe symptom in the blepharitis slit-lamp examination at
baseline (bibrocathol: 97.0 %, placebo: 97.9 %). At V4
(LOCF), only 11 patients (11.0 %) in the bibrocathol group
suffered from one such symptom. In the placebo group,
still
31 (32.0 %) patients were affected with 12 patients having
more than one severe or very severe symptom (see Fig.
3 for frequency distribution). The group difference at V4
(LOCF) was statistically significant with p < 0.001 in all
four signs/symptoms (Chi-square test).
Demographic
variables
Statistic
Bibrocathol 2 %
n 0 100
Placebo
n 0 97
Total
n 0 197
Age (years)
M SD
Median
Range
57.3 18.15
61.0
1987
54.1 17.90
56.0
2086
55.7 18.05
59.0
1987
n (%)
n (%)
42 (42.0)
58 (58.0)
45 (46.4)
52 (53.6)
87 (44.2)
110 (55.8)
n (%)
n (%)
M SD
Median
Range
99 (99.0)
1 (1.0)
27.4 3.58
27.7
16.637.1
97 (100)
26.6 3.63
26.4
17.535.4
196 (99.5)
1 (0.5)
27.0 3.61
27.1
16.637.1
Sex
Male
Female
Ethnicity
Caucasian
Asian
BMI (kg/m2)
range minimummaximum
Discussion
The results of this study clearly demonstrate that
bibrocathol
2 % ointment was superior over vehicle ointment (placebo)
with regard to improvement of blepharitis symptoms after
2 weeks of treatment in a patient population suffering from
acute palpebral inflammation but not requiring antibiotic
treatment. As infection plays a crucial role in the etiology
of blepharitis, adding antiseptic agents to standard lid hygiene seems to be a reasonable and effective treatment
option, especially as it avoids the risk of bacterial
resistance and substance hypersensitivity associated with
topical use of
Fig. 2 Single scores from slitlamp examination (ITT)
antibiotics, at the same time decreasing the risk of sideeffects of antibiotics [1, 2, 9, 10]. Bibrocathol 2 % is an
antiseptic ointment with disinfectant, anti-inflammatory,
astringent, and secretion-inhibitory effects. Its mechanism
of action is determined by its structural components, mainly
tetrabromopyrocatechol and bismuth hydroxide. Bacterial
invasion is prevented by protein denaturation and surface
tissue diminution. In addition, the astringent effect on small
vessels reduces local inflammation and secretion [11].
Therefore, no resistance to this antiseptic agent can
develop.
This mechanism of action is different from the antibacterial effect of antibiotics. Previous in-vitro microbiological
tests had shown a potential of an antibacterial effect (data
on file). To confirm this property in a clinical setting,
palpebral smears were taken during this study. However,
these tests could not show a relevant difference between
active treat- ment and placebo. It was concluded from these
tests that the clinical mode of action of bibrocathol 2 % is
not a direct
Change from
BL (LOCF)
Statistic
Bibrocathol 2 %
n 0 100
Placebo
n 0 97
Edema
M SD
Median (range)
LS mean (95 %
p value
Cohens d
M SD
Median (range)
LS mean (95 %
p value
Cohens d
M SD
Median (range)
LS mean (95 %
p value
Cohens d
M SD
Median (range)
LS mean (95 %
p value
1.20 1.20
1.00 (41)
Cohens d
M SD
1.86 0.89
2.00 (41)
0.70 (0.88; 0.51)
<0.0001
0.60
1.77 0.85
2.00 (40)
0.57 (0.75; 0.38)
<0.0001
0.54
1.74 0.89
2.00 (40)
0.47 (0.65; 0.29)
<0.0001
0.50
1.46 0.80
1.00 (40)
0.62 (0.82; 0.43)
<0.0001
0.57
4.69 1.95
Median (range)
LS mean (95 % CI)
p value
Cohens d
5.00 (101)
1.86 (2.25; 1.46)
<0.0001
0.81
2.00 (91)
Difference
Erythema
Difference
Debris
Difference
VAS (010)
Difference
antibacterial effect comparable to antibiotic treatment. However, further evidence is needed to support the
pharmacody- namic effect of bibrocathol.
The observed treatment differences between
bibrocathol
2 % and placebo are clinically relevant in the total
population
Fig. 3 Frequency distribution
of patients with severe or
very severe symptoms at
baseline and last visit
(LOCF) [ITT]
CI)
CI)
CI)
CI)
1.21 1.15
1.00 (40)
1.30 0.82
1.00 (40)
0.90 1.08
1.00 (40)
2.79 2.29
our study, the effect size was 0.73 for the primary
endpoint, which is clearly above the medium level and
close to the requirement for a large effect (d 0.8). Thus,
the superiority of bibrocathol 2 % over placebo is not
only statistically significant but also clinically relevant. On
the other hand, there were very few patients with severe or
very severe symp- toms in the bibrocathol group as
compared to the placebo group although vehicle therapy
also showed a curing effect at the end of the 14-day
treatment period. Additionally, by defining a responder as a
patient with a total score <4 and each of the 4
signs/symptoms being 1, we found 58.0 % respond- ers in
the bibrocathol and 25.8 % responders in the placebo
group (p <0.0001 in Fishers exact test).
The high number of application site reactions or pruritus
in the placebo group may rather be attributable to disease
symp- toms, which did not improve under therapy than to
AEs caused by the placebo ointment, as their occurrence
was associated with a higher blepharitis total score in both
groups (correlation of 0 0.69 for the total sample). This is
in accordance with our expectation that the application of
eye ointment could possibly cause application site
discomfort, which may be perceived more intensely by
patients with no or slow symptom improve- ment than by
patients with fast symptom improvement.
Taking the favorable tolerability and safety of
bibrocathol
2 % eye ointment into account, together with the clinically
relevant efficacy as shown by symptom improvement, it is
concluded that the antiseptic bibrocathol 2 % is an
efficacious therapy of acute forms of blepharitis with a
positive risk benefit ratio. In clinical practice, it can help
to avoid the risks of antibiotic treatment including bacterial
resistance or hyper- sensitivity reactions. Further clinical
investigations may include a long-term follow-up over
several months, and other trials could prove the efficacy of
bibrocathol 2 % in long-term treatment to confirm its
benefits in chronic forms of blepharitis.
Acknowledgments This clinical study was funded by Ursapharm
Arzneimittel GmbH, Saarbrcken, Germany. Franziska Meister, PhD,
a medical writer at RPS, supported the process of manuscript writing
for this article.
Financial Disclosure This clinical trial was sponsored by URSAPHARM Arzneimittel GmbH. There are no other financial relationships with the authors. The authors have full control of all primary
data
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author(s) and the source are credited.
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